Publications by authors named "Martin Heni"

132 Publications

Determinants of hepatic insulin clearance - Results from a Mendelian Randomization study.

Metabolism 2021 Apr 20;119:154776. Epub 2021 Apr 20.

Department of Internal Medicine IV, Division of Endocrinology, Diabetology and Nephrology, University Hospital of Tübingen, Tübingen, Germany; Institute of Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen (IDM), Tübingen, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany. Electronic address:

Aims/hypothesis: Besides insulin resistance, type 2 diabetes associates with decreased hepatic insulin clearance (HIC). We now tested for causal relationship of HIC to liver fat accumulation or features of the metabolic syndrome.

Methods: HIC was derived from oral glucose tolerance tests with the "Oral C-peptide and Insulin Minimal Models" (n = 3311). Liver fat was quantified by magnetic resonance spectroscopy (n = 1211). Mendelian Randomization was performed using established single nucleotide polymorphisms (SNPs; 115 for liver fat, 155 alanine-aminotransferase, 37 insulin sensitivity, 37 insulin secretion, 72 fasting insulin, 5285 BMI, 163 visceral fat, 270 waist circumference, 442 triglycerides, 620 HDL-Cholesterol, 193 C-reactive protein, 53 lipodystrophy-like phenotypes).

Results: HIC associated inversely with liver fat (p < 0.003) and insulin sensitivity (p < 0.0001). Both liver fat and HIC were independently associated with insulin sensitivity (p < 0.0001). Neither liver fat nor alanine-aminotransferase were causally linked to HIC, as indicated by Mendelian Randomization (N = 1054, N = 2254; N = 1985, N = 2251). BMI-related SNPs were causally associated with HIC (N = 2772, N = 2259, p < 0.001) but not waist circumference-SNPs (N = 2751, N = 2280). Genetically determined insulin sensitivity was not causally related to HIC (N = 2752, N = 2286). C-reactive protein and HDL were causally associated with HIC, with higher C-reactive protein and lower HDL leading to higher HIC (N = 2660, N = 2240; N = 2694, N = 2275).

Conclusions: This Mendelian Randomization analysis does not support a causal link between hepatic steatosis and HIC. Other components of the metabolic syndrome seem to compensate peripheral hyperinsulinemia by increasing hepatic insulin extraction.
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http://dx.doi.org/10.1016/j.metabol.2021.154776DOI Listing
April 2021

Pancreatic fat cells of humans with type 2 diabetes display reduced adipogenic and lipolytic activity.

Am J Physiol Cell Physiol 2021 Mar 31. Epub 2021 Mar 31.

German Center for Diabetes Research (DZD e.V.); Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the Eberhard-KarlsUniversity of Tübingen, Neuherberg; Department of Internal Medicine IV, Division of Endocrinology, Diabetology and Nephrology, University Hospital of Eberhard-Karls-University Tübingen, Tübingen, Germany.

Obesity, especially visceral fat accumulation, increases the risk of type 2 diabetes (T2D). The purpose of this study was to investigate the impact of T2D on the pancreatic fat depot. Pancreatic fat pads from 17 partial pancreatectomized patients (PPP) were collected, pancreatic preadipocytes isolated and in vitro differentiated. Patients were grouped using HbA1c into normal glucose tolerant (NGT), prediabetic (PD) and T2D. Transcriptome profiles of preadipocytes and adipocytes were assessed by RNAseq. Insulin sensitivity was estimated by quantifying AKT phosphorylation on western blots. Lipogenic capacity was assessed with oil red O staining, lipolytic activity via fatty acid release. Secreted factors were measured using ELISA. Comparative transcriptome analysis of preadipocytes and adipocytes indicates defective upregulation of genes governing adipogenesis (NR1H3), lipogenesis (FASN, SCD, ELOVL6, FADS1) and lipolysis (LIPE) during differentiation of cells from T2D-PPP. In addition, the ratio of leptin/adiponectin mRNA was higher in T2D than in NGT-PPP. Preadipocytes and adipocytes of NGT-PPP were more insulin sensitive than T2D-PPP cells in regard to AKT phosphorylation. Triglyceride accumulation was similar in NGT and T2D adipocytes. Despite a high expression of the receptors NPR1 and NPR2 in NGT and T2D adipocytes, lipolysis was stimulated by ANP 1.74-fold in NGT cells only. This stimulation was further increased by the PDE5 inhibitor dipyridamole (3.09-fold). Dipyridamole and forskolin increased lipolysis receptor-independently 1.88-fold and 1.48-fold, respectively, solely in NGT cells. In conclusion, the metabolic status persistently affects differentiation and lipolysis of pancreatic adipocytes. These alterations could aggravate the development of T2D.
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http://dx.doi.org/10.1152/ajpcell.00595.2020DOI Listing
March 2021

The hepatokine fetuin-A disrupts functional maturation of pancreatic beta cells.

Diabetologia 2021 Jun 25;64(6):1358-1374. Epub 2021 Mar 25.

Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the Eberhard Karls University of Tuebingen (IDM), Tuebingen, Germany.

Aims/hypothesis: Neonatal beta cells carry out a programme of postnatal functional maturation to achieve full glucose responsiveness. A partial loss of the mature phenotype of adult beta cells may contribute to a reduction of functional beta cell mass and accelerate the onset of type 2 diabetes. We previously found that fetuin-A, a hepatokine increasingly secreted by the fatty liver and a determinant of type 2 diabetes, inhibits glucose-stimulated insulin secretion (GSIS) of human islets. Since fetuin-A is a ubiquitous fetal glycoprotein that declines peripartum, we examined here whether fetuin-A interferes with the functional maturity of beta cells.

Methods: The effects of fetuin-A were assessed during in vitro maturation of porcine neonatal islet cell clusters (NICCs) and in adult human islets. Expression alterations were examined via microarray, RNA sequencing and reverse transcription quantitative real-time PCR (qRT-PCR), proteins were analysed by western blotting and immunostaining, and insulin secretion was quantified in static incubations.

Results: NICC maturation was accompanied by the gain of glucose-responsive insulin secretion (twofold stimulation), backed up by mRNA upregulation of genes governing beta cell identity and function, such as NEUROD1, UCN3, ABCC8 and CASR (Log fold change [LogFC] > 1.6). An active TGFβ receptor (TGFBR)-SMAD2/3 pathway facilitates NICC maturation, since the TGFBR inhibitor SB431542 counteracted the upregulation of aforementioned genes and de-repressed ALDOB, a gene disallowed in mature beta cells. In fetuin-A-treated NICCs, upregulation of beta cell markers and the onset of glucose responsiveness were suppressed. Concomitantly, SMAD2/3 phosphorylation was inhibited. Transcriptome analysis confirmed inhibitory effects of fetuin-A and SB431542 on TGFβ-1- and SMAD2/3-regulated transcription. However, contrary to SB431542 and regardless of cMYC upregulation, fetuin-A inhibited beta cell proliferation (0.27 ± 0.08% vs 1.0  ± 0.1% Ki67-positive cells in control NICCs). This effect was sustained by reduced expression (LogFC ≤ -2.4) of FOXM1, CENPA, CDK1 or TOP2A. In agreement, the number of insulin-positive cells was lower in fetuin-A-treated NICCs than in control NICCs (14.4 ± 1.2% and 22.3 ± 1.1%, respectively). In adult human islets fetuin-A abolished glucose responsiveness, i.e. 1.7- and 1.1-fold change over 2.8 mmol/l glucose in control- and fetuin-A-cultured islets, respectively. In addition, fetuin-A reduced SMAD2/3 phosphorylation and suppressed expression of proliferative genes. Of note, in non-diabetic humans, plasma fetuin-A was negatively correlated (p = 0.013) with islet beta cell area.

Conclusions/interpretation: Our results suggest that the perinatal decline of fetuin-A relieves TGFBR signalling in islets, a process that facilitates functional maturation of neonatal beta cells. Functional maturity remains revocable in later life, and the occurrence of a metabolically unhealthy milieu, such as liver steatosis and elevated plasma fetuin-A, can impair both function and adaptive proliferation of beta cells.

Data Availability: The RNAseq datasets and computer code produced in this study are available in the Gene Expression Omnibus (GEO): GSE144950; https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE144950.
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http://dx.doi.org/10.1007/s00125-021-05435-1DOI Listing
June 2021

Low-density lipoprotein cholesterol is associated with insulin secretion.

J Clin Endocrinol Metab 2021 Mar 10. Epub 2021 Mar 10.

Institute for Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany.

Objective: Pharmacological lowering of LDL cholesterol potently reduces cardiovascular risk while concurrently increasing type 2 diabetes risk. The aim of this study was to investigate the relationship between LDL cholesterol concentrations and insulin secretion and glucagon levels.

Methods: 3,039 subjects without cholesterol lowering therapy, but with increased risk for diabetes, underwent routine blood tests and a 5-point oral glucose tolerance test (OGTT). Glucagon concentrations, insulin secretion and insulin clearance indices were derived from the OGTT.

Results: There was no association between LDL cholesterol and fasting glucagon (p=0.7, ß=-0.01) or post glucose load glucagon levels (p=0.7, ß=-0.07), but we detected significant positive associations of LDL cholesterol and C-peptide-based indices of insulin secretion (AUCC-Peptide(0-30min)/AUCGlucose(0-30min): p=0.0001, ß=0.06; AUCC-Peptide(0-120min)/AUCGlucose(0-120min): p<0.0001, ß=-0.08). In contrast we found a negative association of insulin-based insulin secretion indices with LDL concentrations (Insulinogenic index: p=0.014, ß=-0.04; disposition index: p=0.0005, ß=-0.06). Though, LDL cholesterol levels were positively associated with insulin clearance assessed from C-peptide and insulin concentrations, both in the fasting state and post glucose load (p<0.0001, ß=0.09 and p<0.0001, ß=0.06, respectively).

Conclusion: As C-peptide based indices reflect insulin secretion independent of hepatic clearance, our results indicate lower insulin secretion in case of lesser LDL cholesterol. This could explain deteriorating glycemic control in response to cholesterol lowering drugs.
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http://dx.doi.org/10.1210/clinem/dgab147DOI Listing
March 2021

Lifestyle intervention improves prothrombotic coagulation profile in individuals at high-risk for type 2 diabetes.

J Clin Endocrinol Metab 2021 Feb 28. Epub 2021 Feb 28.

Institute for Clinical Chemistry and Pathobiochemistry, Department for Diagnostic Laboratory Medicine, University Hospital Tübingen, Germany.

Aims: Patients with obesity and insulin resistance are at higher risk for arterial and venous thrombosis due to a prothrombotic state. If this is reversible by lifestyle intervention was addressed in the current study and potential underlying associations were elucidated.

Subjects And Methods: One-hundred individuals with impaired glucose tolerance or impaired fasting plasma glucose participated in a 1-year lifestyle intervention, including precise metabolic phenotyping and MRT-based determination of liver fat content as well as a comprehensive analysis of coagulation parameters before and after this intervention.

Results: During the lifestyle intervention significant reductions in coagulation factor activities (II, VII, VIII, IX, XI and XII) were observed. Accordingly, prothrombin time (PT%) and activated partial thromboplastin time (aPTT) were slightly decreased and prolonged, respectively. Moreover, PAI-1, vWF and also protein C and protein S decreased. Fibrinogen, antithrombin, D-Dimer and FXIII remained unchanged. Searching for potential regulators, especially weight loss, but also liver fat reduction, improved insulin sensitivity and decreased low-grade inflammation were linked to favorable changes in hemostasis parameters.

Independent Of Weight Loss: , liver fat reduction (FII, protein C, protein S, PAI-1, vWF), improved insulin sensitivity (protein S, PAI-1) and reduced low-grade inflammation (PT%, aPTT, FVIII/IX/XI/XII, vWF) were identified as single potential regulators.

Conclusions: Lifestyle intervention is able to improve a prothrombotic state in individuals at high-risk for type 2 diabetes. Besides body weight, liver fat content, insulin sensitivity and systemic low-grade inflammation are potential mechanisms for improvements in hemostasis and could represent future therapeutic targets.
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http://dx.doi.org/10.1210/clinem/dgab124DOI Listing
February 2021

Low-fat hypocaloric diet reduces neprilysin in overweight and obese human subjects.

ESC Heart Fail 2021 Apr 27;8(2):938-942. Epub 2021 Feb 27.

Section of Metabolic and Vascular Medicine, Medical Clinic III, University Hospital Carl Gustav Carus, TU Dresden, Dresden, Germany.

Aims: Neprilysin (NEP), a zinc metallopeptidase, degrades a variety of bioactive peptides including natriuretic peptides terminating their biological action on arterial blood pressure and natriuresis. Pharmacological inhibition of NEP reduces mortality in patients with heart failure with reduced ejection fraction. Physiological interventions reducing NEP levels are unknown in humans. Because obesity leads to increased NEP levels and increases the risk for heart failure, we hypothesized that weight loss reduces NEP concentrations in plasma and tissue.

Methods And Results: We randomized overweight to obese human subjects to a low-fat or low-carbohydrate hypocaloric 6 month weight loss intervention. Soluble NEP was determined in plasma, and NEP mRNA was analysed from subcutaneous adipose tissue before and after diet. Low-fat diet-induced weight loss reduced soluble NEP levels from 0.83 ± 0.18 to 0.72 ± 0.18 μg/L (P = 0.038), while subcutaneous adipose tissue NEP mRNA expression was reduced by both dietary interventions [21% (P = 0.0057) by low-fat diet and 16% (P = 0.048) by low-carbohydrate diet]. We also analysed the polymorphisms of the gene coding for NEP, rs9827586 and rs701109, known to be associated with plasma NEP levels. For both single-nucleotide polymorphisms, minor allele carriers (A/A) had higher baseline plasma NEP levels (rs9827586: β = 0.53 ± 0.23, P < 0.0001; rs701109: β = 0.43 ± 0.22, P = 0.0016), and minor allele carriers of rs9827586 responded to weight loss with a larger NEP reduction (rs9827586: P = 0.0048).

Conclusions: Our study identifies weight loss via a hypocaloric low-fat diet as the first physiological intervention in humans to reduce NEP in plasma and adipose tissue. Specific single-nucleotide polymorphisms further contribute to the decrease. Our findings may help to explain the beneficial effect of weight loss on cardiac function in patients with heart failure.
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http://dx.doi.org/10.1002/ehf2.13220DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8006681PMC
April 2021

No Effect of Lifestyle Intervention during Third Trimester on Brain Programming in Fetuses of Mothers with Gestational Diabetes.

Nutrients 2021 Feb 8;13(2). Epub 2021 Feb 8.

Helmholtz Center Munich at the University of Tübingen/fMEG Center, Institute for Diabetes Research and Metabolic Diseases, 72076 Tübingen, Germany.

Maternal metabolism and intrauterine conditions influence development of health and disease in offspring, leading to metabolic, physiologic, and/or epigenetic adaptation of the fetus. Maternal gestational diabetes (GDM) leads to higher incidence of obesity and type 2 diabetes in offspring. We have previously shown that fetuses of insulin-resistant mothers with GDM have a delayed reaction to auditory stimuli in the postprandial state, indicating a fetal central insulin resistance. We tested whether this effect could be influenced by a lifestyle intervention in mothers with GDM, including diet counselling and regular blood glucose measurements. We measured fetal brain activity over the course of a maternal glucose challenge, at two measurement time points (baseline at an average of 29 weeks of gestation and follow-up after 4 weeks) in mothers with GDM and mothers with normal glucose tolerance (NGT). Data from eight mothers were able to be included. Fetuses of GDM mothers showed longer latencies than those of NGT mothers postprandially at both measurement time points during the third trimester and did not show a difference in response patterns between baseline and after 4 weeks. Maternal postprandial blood glucose and insulin values did not change from baseline to follow-up either. While the overall intervention seems to have been effective, it does not appear to have influenced the fetal postprandial brain responses. This might have been because interventions for GDM take place relatively late in pregnancy. Future research should focus on maternal lifestyle interventions as early as possible during gestation, or even prenatally.
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http://dx.doi.org/10.3390/nu13020556DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7915982PMC
February 2021

Pathophysiology-based subphenotyping of individuals at elevated risk for type 2 diabetes.

Nat Med 2021 01 4;27(1):49-57. Epub 2021 Jan 4.

Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany.

The state of intermediate hyperglycemia is indicative of elevated risk of developing type 2 diabetes. However, the current definition of prediabetes neither reflects subphenotypes of pathophysiology of type 2 diabetes nor is predictive of future metabolic trajectories. We used partitioning on variables derived from oral glucose tolerance tests, MRI-measured body fat distribution, liver fat content and genetic risk in a cohort of extensively phenotyped individuals who are at increased risk for type 2 diabetes to identify six distinct clusters of subphenotypes. Three of the identified subphenotypes have increased glycemia (clusters 3, 5 and 6), but only individuals in clusters 5 and 3 have imminent diabetes risks. By contrast, those in cluster 6 have moderate risk of type 2 diabetes, but an increased risk of kidney disease and all-cause mortality. Findings were replicated in an independent cohort using simple anthropomorphic and glycemic constructs. This proof-of-concept study demonstrates that pathophysiological heterogeneity exists before diagnosis of type 2 diabetes and highlights a group of individuals who have an increased risk of complications without rapid progression to overt type 2 diabetes.
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http://dx.doi.org/10.1038/s41591-020-1116-9DOI Listing
January 2021

Reduced insulin clearance is linked to subclinical atherosclerosis in individuals at risk for type 2 diabetes mellitus.

Sci Rep 2020 12 31;10(1):22453. Epub 2020 Dec 31.

Institute of Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Center Munich at the University of Tübingen, Otfried-Müller-Str. 10, 72076, Tübingen, Germany.

Hyperglycemia and insulin resistance contribute to vascular damage and are regulated by different pathophysiological processes. The aim of the study was to systematically investigate the relative contributions of multiple fasting state- and oral glucose tolerance test (oGTT)-derived glycemic traits to carotid intima-media thickness (cIMT), a surrogate parameter of subclinical atherosclerosis, in individuals with increased risk for type 2 diabetes mellitus (T2D). 667 volunteers (417 women and 250 men, mean age 44.1 years), who were free of cardiovascular disease (CVD), were included in this cross-sectional study. Glucose tolerance, insulin sensitivity, insulin secretion and insulin clearance were assessed by frequently sampled 75 g oGTT. CIMT was measured by high-resolution ultrasound. Insulin clearance was associated with cIMT in univariate analysis (ß = - 0.17, p < 0.0001) and in a stepwise regression analysis on 15 variables possibly affecting cIMT, age (r = 0.3923, p < 0.0001), insulin clearance (r = 0.4564, p < 0.0001), systolic blood pressure (r = 0.4733, p < 0.0001), body mass index (BMI) (r = 0.4804, p = 0.002), gender (r = 0.4831, p = 0.013), and fasting insulin clearance (r = 0.4857, p = 0.030) turned out to be significant determinants of cIMT. In a cross-validated model resulting from this analysis, insulin clearance was found to be an independent determinant of cIMT (ß = - 0.16, p < 0.0001) even after adjusting for traditional CVD risk factors. Reduced insulin clearance may be an early marker of damage on the vasculature, independent of classical CVD risk factors. Reduced insulin clearance should be considered with regard to vascular insulin resistance.
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http://dx.doi.org/10.1038/s41598-020-80581-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7775444PMC
December 2020

Elevated Circulating Glutamate Is Associated With Subclinical Atherosclerosis Independently of Established Risk Markers: A Cross-Sectional Study.

J Clin Endocrinol Metab 2021 Jan;106(2):e982-e989

Institute of Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Centre Munich, Tübingen, Germany.

Objective: Elevated plasma glutamate levels are associated with an increased risk of cardiovascular disease (CVD). Because plasma glutamate levels are also strongly associated with visceral adiposity, nonalcoholic fatty liver disease, insulin resistance, and high circulating levels of branched-chain amino acids (BCAAs), it is unknown to what extent elevated circulating glutamate is an independent marker of an increased risk of atherosclerosis.

Methods: Plasma levels of glutamate and BCAAs were measured in 102 individuals who were precisely phenotyped for body fat mass and distribution (magnetic resonance [MR] tomography), liver fat content (1H-MR spectroscopy), insulin sensitivity (oral glucose tolerance test and hyperinsulinemic, euglycemic clamp [N = 57]), and carotid intima media thickness (cIMT).

Results: Plasma glutamate levels, adjusted for age, sex, body fat mass, and visceral fat mass, correlated positively with liver fat content and cIMT (all std β ≥ .22, all P ≤ .023) and negatively with insulin sensitivity (std β ≤ -.31, P ≤ .002). Glutamate levels also were associated with cIMT, independently of additional adjustment for liver fat content, insulin sensitivity and BCAAs levels (std β ≥ .24, P ≤ .02). Furthermore, an independent positive association of glutamate and interleukin-6 (IL-6) levels was observed (N = 50; std β = .39, P = .03). Although glutamate, adjusted for age, sex, body fat mass, and visceral fat mass, also correlated positively with cIMT in this subgroup (std β = .31, P = .02), after additional adjustment for the parameters liver fat content, insulin sensitivity, BCAAs, or IL-6 levels, adjustment for IL-6 most strongly attenuated this relationship (std β = .28, P = .05).

Conclusions: Elevated plasma glutamate levels are associated with increased cIMT, independently of established CVD risk factors, and this relationship may in part be explained by IL-6-associated subclinical inflammation.
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http://dx.doi.org/10.1210/clinem/dgaa898DOI Listing
January 2021

No modulation of postprandial metabolism by transcutaneous auricular vagus nerve stimulation: a cross-over study in 15 healthy men.

Sci Rep 2020 11 24;10(1):20466. Epub 2020 Nov 24.

Department of Internal Medicine IV, Division of Diabetology, Endocrinology and Nephrology, University Hospital Tübingen, Otfried-Müller-Str. 10, 72076, Tübingen, Germany.

Experimental evidence suggests a crucial role of the autonomic nervous system in whole body metabolism with major regulatory effects of the parasympathetic branch in postprandial adaptation. However, the relative contribution of this mechanism is still not fully clear in humans. We therefore compared the effects of transcutaneous auricular vagus nerve stimulation (taVNS, Cerbomed Nemos) with sham stimulation during an oral glucose tolerance test in a randomized, single-blind, cross-over design in 15 healthy lean men. Stimulation was performed for 150 min, 30 min before and during the entire oral glucose tolerance test with stimulation cycles of 30 s of on-phase and 30 s of off-phase and a 25 Hz impulse. Heart rate variability and plasma catecholamine levels were assessed as proxies of autonomic tone in the periphery. Neither analyzed heart rate variability parameters nor plasma catecholamine levels were significantly different between the two conditions. Plasma glucose, insulin sensitivity and insulin secretion were also comparable between conditions. Thus, the applied taVNS device or protocol was unable to achieve significant effects on autonomic innervation in peripheral organs. Accordingly, glucose metabolism remained unaltered. Therefore, alternative approaches are necessary to investigate the importance of the autonomic nervous system in postprandial human metabolism.
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http://dx.doi.org/10.1038/s41598-020-77430-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686306PMC
November 2020

Increased Expressions of Matrix Metalloproteinases (MMPs) in Prostate Cancer Tissues of Men with Type 2 Diabetes.

Biomedicines 2020 Nov 16;8(11). Epub 2020 Nov 16.

Department of Internal Medicine IV, Division of Diabetology, Endocrinology and Nephrology, University Hospital Tübingen, 72076 Tübingen, Germany.

Type 2 diabetes (T2D) is associated with worse prognosis of prostate cancer (PCa). The molecular mechanisms behind this association are still not fully understood. The aim of this study was to identify key factors, which contribute to the more aggressive PCa phenotype in patients with concurrent T2D. Therefore, we investigated benign and PCa tissue of PCa patients with and without diabetes using real time qPCR. Compared to patients without diabetes, patients with T2D showed a decreased E-cadherin/N-cadherin (CDH1/CDH2) ratio in prostate tissue, indicating a switch of epithelial-mesenchymal transition (EMT), which is a pivotal process in carcinogenesis. In addition, the gene expression levels of matrix metalloproteinases () and CC chemokine ligands () were higher in prostate samples of T2D patients. Next, prostate adenocarcinoma PC3 cells were treated with increasing glucose concentrations to replicate hyperglycemia in vitro. In these cells, high glucose induced expressions of and , which showed significant positive associations with the proliferation marker proliferating cell nuclear antigen (). These results indicate that in prostate tissue of men with T2D, hyperglycemia may induce EMT, increase and gene expressions, which in turn activate invasion and inflammatory processes accelerating the progression of PCa.
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http://dx.doi.org/10.3390/biomedicines8110507DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7696165PMC
November 2020

Insulin sensitivity predicts cognitive decline in individuals with prediabetes.

BMJ Open Diabetes Res Care 2020 11;8(2)

Department of Internal Medicine IV, University Hospital of Tübingen, Tübingen, Germany

Introduction: Epidemiological studies indicate an association between type 2 diabetes and cognitive dysfunction that appear to start already in the prediabetic state. Although cross-sectional studies have linked insulin resistance to impaired cognition, the potential predictive value of insulin resistance has not yet been sufficiently studied longitudinally without confounding by overt diabetes (and its pharmacological treatment).

Research Design And Methods: We investigated longitudinal data from participants of the 'Tübinger Evaluation of Risk Factors for Early Detection of Neurodegeneration' Study. Subjects underwent a neurocognitive assessment battery (CERAD Plus battery; Consortium to Establish a Registry for Alzheimer's Disease) at baseline and followed every 2 years (median follow-up 4.0 Q1-3: 2.2-4.3 years). Subjects within a pre-diabetic glycated hemoglobin range of 5.6%-6.5% underwent 5-point 75 g oral glucose tolerance tests (OGTTs) with assessment of insulin sensitivity and insulin secretion (n=175). Subjects with newly diagnosed diabetes mellitus or with major depressivity (Beck Depression Inventory >20) were excluded (n=15). Data were analyzed by mixed models using sex, age and glycemic trait as fixed effects. Subject and time since first measurement were used as random effects.

Results: Insulin sensitivity was positively associated with the CERAD sum score (higher is better) in a time-dependent manner (p=0.0057). This result is mainly driven by a steeper decrease in the memory domain associated with lower insulin sensitivity (p=0.029). The interaction between age and insulin sensitivity was independent of glycemia (p=0.02). There was also no association between insulin secretion and cognition.

Conclusions: Insulin resistance rather than sole elevation of blood glucose predicts cognitive decline, specifically in the memory domain, in persons with prediabetes. Treatments of diabetes that improve insulin sensitivity might therefore have the potential to postpone or even prevent cognitive decline in patients with diabetes.
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http://dx.doi.org/10.1136/bmjdrc-2020-001741DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7674089PMC
November 2020

Diabetes type 2 risk gene Dusp8 is associated with altered sucrose reward behavior in mice and humans.

Brain Behav 2021 Jan 1;11(1):e01928. Epub 2020 Nov 1.

Research Unit Neurobiology of Diabetes, Helmholtz Zentrum München, Neuherberg, Germany.

Background: Dusp8 is the first GWAS-identified gene that is predominantly expressed in the brain and has previously been linked with the development of diabetes type 2 in humans. In this study, we unravel how Dusp8 is involved in the regulation of sucrose reward behavior.

Methods: Female, chow-fed global Dusp8 WT and KO mice were tested in an observer-independent IntelliCage setup for self-administrative sucrose consumption and preference followed by a progressive ratio task with restricted sucrose access to monitor seeking and motivation behavior. Sixty-three human carriers of the major C and minor T allele of DUSP8 SNP rs2334499 were tested for their perception of food cues by collecting a rating score for sweet versus savory high caloric food.

Results: Dusp8 KO mice showed a comparable preference for sucrose, but consumed more sucrose compared to WT mice. In a progressive ratio task, Dusp8 KO females switched to a "trial and error" strategy to find sucrose while control Dusp8 WT mice kept their previously established seeking pattern. Nonetheless, the overall motivation to consume sucrose, and the levels of dopaminergic neurons in the brain areas NAcc and VTA were comparable between genotypes. Diabetes-risk allele carriers of DUSP8 SNP rs2334499 preferred sweet high caloric food compared to the major allele carriers, rating scores for savory food remained comparable between groups.

Conclusion: Our data suggest a novel role for Dusp8 in the perception of sweet high caloric food as well as in the control of sucrose consumption and foraging in mice and humans.
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http://dx.doi.org/10.1002/brb3.1928DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7821601PMC
January 2021

Ectopic fat accumulation in human astrocytes impairs insulin action.

R Soc Open Sci 2020 Sep 16;7(9):200701. Epub 2020 Sep 16.

Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany.

Astrocytes provide neurons with structural support and energy in form of lactate, modulate synaptic transmission, are insulin sensitive and act as gatekeeper for water, ions, glutamate and second messengers. Furthermore, astrocytes are important for glucose sensing, possess neuroendocrine functions and also play an important role in cerebral lipid metabolism. To answer the question, if there is a connection between lipid metabolism and insulin action in human astrocytes, we investigated if storage of ectopic lipids in human astrocytes has an impact on insulin signalling in those cells. Human astrocytes were cultured in the presence of a lipid emulsion, consisting of fatty acids and triglycerides, to induce ectopic lipid storage. After several days, cells were stimulated with insulin and gene expression profiling was performed. In addition, phosphorylation of Akt as well as glycogen synthesis and cell proliferation was assessed. Ectopic lipid storage was detected in human astrocytes after lipid exposure and lipid storage was persistent even when the fat emulsion was removed from the cell culture medium. Chronic exposure to lipids induced profound changes in the gene expression profile, whereby some genes showed a reversible gene expression profile upon removal of fat, and some did not. This included FOXO-dependent expression patterns. Furthermore, insulin-induced phosphorylation of Akt was diminished and also insulin-induced glycogen synthesis and proliferation was impaired in lipid-laden astrocytes. Chronic lipid exposure induces lipid storage in human astrocytes accompanied by insulin resistance. Analyses of the gene expression pattern indicated the potential of a partially reversible gene expression profile. Targeting astrocytic insulin resistance by reducing ectopic lipid load might represent a promising treatment target for insulin resistance of the brain in obesity, diabetes and neurodegeneration.
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http://dx.doi.org/10.1098/rsos.200701DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7540778PMC
September 2020

Characterization of Hormone-Dependent Pathways in Six Human Prostate-Cancer Cell Lines: A Gene-Expression Study.

Genes (Basel) 2020 Oct 7;11(10). Epub 2020 Oct 7.

Department of Internal Medicine IV, Division of Diabetology, Endocrinology, and Nephrology, University Hospital Tübingen, 72076 Tübingen, Germany.

Prostate cancer (PCa), the most incident cancer in men, is tightly regulated by endocrine signals. A number of different PCa cell lines are commonly used for in vitro experiments, but these are of diverse origin, and have very different cell-proliferation rates and hormone-response capacities. By analyzing the gene-expression pattern of main hormone pathways, we systematically compared six PCa cell lines and parental primary cells. We compared these cell lines (i) with each other and (ii) with PCa tissue samples from 11 patients. We found major differences in the gene-expression levels of androgen, insulin, estrogen, and oxysterol signaling between PCa tissue and cell lines, and between different cell lines. Our systematic characterization gives researchers a solid basis to choose the appropriate PCa cell model for the hormone pathway of interest.
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http://dx.doi.org/10.3390/genes11101174DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7599530PMC
October 2020

Investigating obesity-associated brain inflammation using quantitative water content mapping.

J Neuroendocrinol 2020 12 6;32(12):e12907. Epub 2020 Oct 6.

Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany.

There is growing evidence that obesity is associated with inflammation in the brain, which could contribute to the pathogenesis of obesity. In humans, it is challenging to detect brain inflammation in vivo. Recently, quantitative magnetic resonance imaging (qMRI) has emerged as a tool for characterising pathophysiological processes in the brain with reliable and reproducible measures. Proton density imaging provides quantitative assessment of the brain water content, which is affected in different pathologies, including inflammation. We enrolled 115 normal weight, overweight and obese men and women (body mass index [BMI] range 20.1-39.7 kg m , age range 20-75 years, 60% men) to acquire cerebral water content mapping in vivo using MRI at 3 Tesla. We investigated potential associations between brain water content with anthropometric measures of obesity, body fat distribution and whole-body metabolism. No global changes in water content were associated with obesity. However, higher water content values in the cerebellum, limbic lobe and sub-lobular region were detected in participants with higher BMI, independent of age. More specifically, the dorsal striatum, hypothalamus, thalamus, fornix, anterior limb of the internal capsule and posterior thalamic radiation showed the strongest relationship with BMI, independent of age. In a subgroup with available measurements (n = 50), we identified visceral adipose tissue to be the strongest tested link between higher water content values and obesity. Individuals with metabolic syndrome had the highest water content values in the hypothalamus and the fornix. There is accumulating evidence that inflammation of the hypothalamus contributed to obesity-associated insulin resistance in that area. Whether brain inflammation is a cause or consequence of obesity in humans still needs to be investigated using a longitudinal study design. Using qMRI, we were able to detect marked water content changes in young and older obese adults, which is most likely the result of chronic low-grade inflammation.
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http://dx.doi.org/10.1111/jne.12907DOI Listing
December 2020

Considering Insulin Secretory Capacity as Measured by a Fasting C-Peptide/Glucose Ratio in Selecting Glucose-Lowering Medications.

Exp Clin Endocrinol Diabetes 2020 Sep 18. Epub 2020 Sep 18.

German Center for Diabetes Research (DZD), Neuherberg.

Type 2 diabetes mellitus is a heterogeneous disease. Recently introduced new subclassifications promise more efficacious, tailored treatments which could complement current guidelines. In the differentiation of the new diabetes subphenotypes, assessment of insulin secretion is one of the essential components. Based on a large number of insulin secretion measurements, we propose fasting C-peptide/glucose ratio (CGR) as an adequate and practicable estimate of insulin secretion. CGR discriminates insulin deficiency from insulin hypersecretion. We suggest using insulin secretion, determined from CGR, as an essential input for therapeutic decisions at the beginning or modification of diabetes treatment. Furthermore, we propose 3 practical steps to guide decisions in the subtype-specific therapy of diabetes mellitus. The first step consists of detecting insulin deficiency indicated by a low CGR with the need for immediate insulin therapy. The second step is related to high CGR and aims at lowering cardiovascular risk associated with diabetes. The third step is the consideration of a de-escalation of glucose-lowering therapy in individuals with mild diabetes subphenotypes.
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http://dx.doi.org/10.1055/a-1242-9809DOI Listing
September 2020

Transcript Levels of Aldo-Keto Reductase Family 1 Subfamily C (AKR1C) Are Increased in Prostate Tissue of Patients with Type 2 Diabetes.

J Pers Med 2020 Sep 12;10(3). Epub 2020 Sep 12.

Department of Internal Medicine IV, Division of Endocrinology, Diabetology and Nephrology, University Hospital Tübingen, 72076 Tübingen, Germany.

Aldo-keto reductase family 1 (AKR1) enzymes play a crucial role in diabetic complications. Since type 2 diabetes (T2D) is associated with cancer progression, we investigated the impact of diabetes on gene expression in the context of prostate cancer (PCa) development. In this study, we analyzed benign (BEN) prostate and PCa tissue of patients with and without T2D. Furthermore, to replicate hyperglycemia in vitro, we treated the prostate adenocarcinoma cell line PC3 with increasing glucose concentrations. Gene expression was quantified using real-time qPCR. In the prostate tissue of patients with T2D, and transcripts were higher compared to samples of patients without diabetes. In PC3 cells, high glucose treatment induced the gene expression levels of , and . Furthermore, both in human tissue and in PC3 cells, the transcript levels of and showed positive associations with oncogenes, which are involved in proliferation processes and HIF1α and NFκB pathways. These results indicate that in the prostate glands of patients with T2D, hyperglycemia could play a pivotal role by inducing the expression of and . The higher transcript level of was furthermore associated with upregulated HIF1α and NFκB pathways, which are major drivers of PCa carcinogenesis.
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http://dx.doi.org/10.3390/jpm10030124DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7564141PMC
September 2020

The TUDID Study - Background and Design of a Prospective Cohort.

Exp Clin Endocrinol Diabetes 2020 Sep 10. Epub 2020 Sep 10.

Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany.

Prevalence of both type 1 and type 2 diabetes mellitus is growing worldwide and one major cause for morbidity and mortality. However, not every patient develops diabetes-related complications, but causes for the individual susceptibility are still not fully understood. As a platform to address this, we initiated the TUDID (TUebingen DIabetes Database) study, a prospective, monocentric, observational study that includes adults with diabetes mellitus who are treated in the inpatient clinic of a University Hospital in southern Germany. Besides a thorough clinical examination and extensive laboratory tests (with integrated biobanking), major study focuses are the kidneys, the eyes, the vasculature as well as cognition and mood where standardized investigations for early stages for diabetes complications are performed. Analyses of the data generated by this precise characterization of diabetes-related complications will contribute to our understanding of the development and course of such complications, and thus facilitate the implementation of tailored treatment options that can reduce the risk and severity of diabetes-related complications.
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http://dx.doi.org/10.1055/a-1221-9618DOI Listing
September 2020

Response of Mitochondrial Respiration in Adipose Tissue and Muscle to 8 Weeks of Endurance Exercise in Obese Subjects.

J Clin Endocrinol Metab 2020 11;105(11)

Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Zentrum München at the University of Tübingen, Tübingen, Germany.

Context: Exercise training improves glycemic control and increases mitochondrial content and respiration capacity in skeletal muscle. Rodent studies suggest that training increases mitochondrial respiration in adipose tissue.

Objective: To assess the effects of endurance training on respiratory capacities of human skeletal muscle and abdominal subcutaneous adipose tissue and to study the correlation with improvement in insulin sensitivity.

Design: Using high-resolution respirometry, we analyzed biopsies from 25 sedentary (VO2 peak 25.1 ± 4.0 VO2 mL/[kg*min]) subjects (16 female, 9 male; 29.8 ± 8.4 years) with obesity (body mass index [BMI] 31.5 ± 4.3 kg/m2), who did not have diabetes. They performed a supervised endurance training over 8 weeks (3 × 1 hour/week at 80% VO2 peak).

Results: Based on change in insulin sensitivity after intervention (using the Matsuda insulin sensitivity index [ISIMats]), subjects were grouped in subgroups as responders (>15% increase in ISIMats) and low-responders. The response in ISIMats was correlated to a reduction of subcutaneous and visceral adipose tissue volume. Both groups exhibited similar increases in fitness, respiratory capacity, and abundance of mitochondrial enzymes in skeletal muscle fibers. Respiratory capacities in subcutaneous adipose tissue were not altered by the intervention. Compared with muscle fibers, adipose tissue respiration showed a preference for β-oxidation and complex II substrates. Respiratory capacities were higher in adipose tissue from female participants.

Conclusion: Our data show that the improvement of peripheral insulin sensitivity after endurance training is not directly related to an increase in mitochondrial respiratory capacities in skeletal muscle and occurs without an increase in the respiratory capacity of subcutaneous adipose tissue.
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http://dx.doi.org/10.1210/clinem/dgaa571DOI Listing
November 2020

Type 2 diabetes risk gene Dusp8 regulates hypothalamic Jnk signaling and insulin sensitivity.

J Clin Invest 2020 11;130(11):6093-6108

Neurobiology of Stress Resilience, Max Planck Institute of Psychiatry, Munich, Germany.

Recent genome-wide association studies (GWAS) identified DUSP8, encoding a dual-specificity phosphatase targeting mitogen-activated protein kinases, as a type 2 diabetes (T2D) risk gene. Here, we reveal that Dusp8 is a gatekeeper in the hypothalamic control of glucose homeostasis in mice and humans. Male, but not female, Dusp8 loss-of-function mice, either with global or corticotropin-releasing hormone neuron-specific deletion, had impaired systemic glucose tolerance and insulin sensitivity when exposed to high-fat diet (HFD). Mechanistically, we found impaired hypothalamic-pituitary-adrenal axis feedback, blunted sympathetic responsiveness, and chronically elevated corticosterone levels driven by hypothalamic hyperactivation of Jnk signaling. Accordingly, global Jnk1 ablation, AAV-mediated Dusp8 overexpression in the mediobasal hypothalamus, or metyrapone-induced chemical adrenalectomy rescued the impaired glucose homeostasis of obese male Dusp8-KO mice, respectively. The sex-specific role of murine Dusp8 in governing hypothalamic Jnk signaling, insulin sensitivity, and systemic glucose tolerance was consistent with functional MRI data in human volunteers that revealed an association of the DUSP8 rs2334499 risk variant with hypothalamic insulin resistance in men. Further, expression of DUSP8 was increased in the infundibular nucleus of T2D humans. In summary, our findings suggest the GWAS-identified gene Dusp8 as a novel hypothalamic factor that plays a functional role in the etiology of T2D.
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http://dx.doi.org/10.1172/JCI136363DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7598066PMC
November 2020

Increased Hepatic ACE2 Expression in NAFL and Diabetes-A Risk for COVID-19 Patients?

Diabetes Care 2020 10 4;43(10):e134-e136. Epub 2020 Aug 4.

Institute for Clinical Chemistry and Pathobiochemistry, University Hospital Tübingen, Tübingen, Germany

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http://dx.doi.org/10.2337/dc20-1458DOI Listing
October 2020

Pancreatic Steatosis Associates With Impaired Insulin Secretion in Genetically Predisposed Individuals.

J Clin Endocrinol Metab 2020 11;105(11)

Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany.

Context: Pancreatic steatosis leading to beta-cell failure might be involved in type 2 diabetes (T2D) pathogenesis.

Objective: We hypothesized that the genetic background modulates the effect of pancreatic fat on beta-cell function and investigated genotype × pancreatic fat interactions on insulin secretion.

Design: Two observational studies.

Setting: University hospital.

Patients Or Participants: A total of 360 nondiabetic individuals with elevated risk for T2D (Tuebingen Family Study [TUEF]), and 64 patients undergoing pancreatectomy (Pancreas Biobank [PB], HbA1c <9%, no insulin therapy).

Main Outcome Measures: Insulin secretion calculated from 5-point oral glucose tolerance test (TUEF) and fasting blood collection before surgery (PB). A genome-wide polygenic score for T2D was computed from 484,788 genotyped variants. The interaction of magnetic resonance imaging-measured and histologically quantified pancreatic fat with the polygenic score was investigated. Partitioned risk scores using genome-wide significant variants were also computed to gain insight into potential mechanisms.

Results: Pancreatic steatosis interacted with genome-wide polygenic score on insulin secretion (P = 0.003), which was similar in the replication cohort with histological measurements (P = 0.03). There was a negative association between pancreatic fat and insulin secretion in participants with high genetic risk, whereas individuals with low genetic risk showed a positive correlation between pancreatic fat and insulin secretion. Consistent interactions were found with insulin resistance-specific and a liver/lipid-specific polygenic scores.

Conclusions: The associations suggest that pancreatic steatosis only impairs beta-cell function in subjects at high genetic risk for diabetes. Genetically determined insulin resistance specifically renders pancreatic fat deleterious for insulin secretion.
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http://dx.doi.org/10.1210/clinem/dgaa435DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7497818PMC
November 2020

Brain substrate metabolism and ß-cell function in humans: A positron emission tomography study.

Endocrinol Diabetes Metab 2020 Jul 19;3(3):e00136. Epub 2020 Apr 19.

Turku PET Centre University of Turku Turku Finland.

Aims: Recent clinical studies have shown enhanced brain glucose uptake during clamp and brain fatty acid uptake in insulin-resistant individuals. Preclinical studies suggest that the brain may be involved in the control of insulin secretion. The aim of this study was to investigate whether brain metabolism assessed as brain glucose and fatty acid uptake is associated with the parameters of β-cell function in humans.

Materials And Methods: We analysed cross-sectional data of 120 subjects across a wide range of BMI and insulin sensitivity. Brain glucose uptake (BGU) was measured during euglycaemic-hyperinsulinaemic clamp (n = 67) and/or during fasting (n = 45) using [F]-fluorodeoxyglucose (FDG) positron emission tomography (PET). In another group of subjects (n = 34), brain fatty acid uptake was measured using [F]-fluoro-6-thia-heptadecanoic acid (FTHA) PET during fasting. The parameters of βcell function were derived from OGTT modelling. Statistical analysis was performed with whole-brain voxel-based statistical parametric mapping.

Results: In non-diabetics, BGU during euglycaemic hyperinsulinaemic clamp correlated positively with basal insulin secretion rate ( = 0.51,  = .0008) and total insulin output ( = 0.51,  = .0008), whereas no correlation was found in type 2 diabetics. BGU during clamp correlated positively with potentiation in non-diabetics ( = 0.33,  = .02) and negatively in type 2 diabetics ( = -0.61,  = .02). The associations in non-diabetics were not explained with whole-body insulin sensitivity or BMI. No correlations were found between baseline (fasting) BGU and basal insulin secretion rate, whereas baseline brain fatty acid uptake correlated directly with basal insulin secretion rate ( = 0.39,  = .02) and inversely with potentiation ( = -0.36,  = .04).

Conclusions: Our study provides coherent, though correlative, evidence that, in humans, the brain may be involved in the control of insulin secretion independently of insulin sensitivity.
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http://dx.doi.org/10.1002/edm2.136DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7375082PMC
July 2020

Human Prostate Cancer is Characterized by an Increase in Urea Cycle Metabolites.

Cancers (Basel) 2020 07 6;12(7). Epub 2020 Jul 6.

Department of Internal Medicine, Division of Endocrinology, Diabetology and Nephrology, University Hospital Tübingen, 72076 Tübingen, Germany.

Despite it being the most common incident of cancer among men, the pathophysiological mechanisms contributing to prostate cancer (PCa) are still poorly understood. Altered mitochondrial metabolism is postulated to play a role in the development of PCa. To determine the key metabolites (which included mitochondrial oncometabolites), benign prostatic and cancer tissues of patients with PCa were analyzed using capillary electrophoresis and liquid chromatography coupled with mass spectrometry. Gene expression was studied using real-time PCR. In PCa tissues, we found reduced levels of early tricarboxylic acid cycle metabolites, whereas the contents of urea cycle metabolites including aspartate, argininosuccinate, arginine, proline, and the oncometabolite fumarate were higher than that in benign controls. Fumarate content correlated positively with the gene expression of oncogenic HIF1α and NFκB pathways, which were significantly higher in the PCa samples than in the benign controls. Furthermore, data from the TCGA database demonstrated that prostate cancer patients with activated NFκB pathway had a lower survival rate. In summary, our data showed that fumarate content was positively associated with carcinogenic genes.
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http://dx.doi.org/10.3390/cancers12071814DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7408908PMC
July 2020

Central nervous pathways of insulin action in the control of metabolism and food intake.

Lancet Diabetes Endocrinol 2020 06;8(6):524-534

Institute for Diabetes Research and Metabolic Diseases, Helmholtz Center Munich, Eberhard Karls University of Tübingen, Tübingen, Germany; Department of Internal Medicine, Division of Endocrinology, Diabetology, and Nephrology, Eberhard Karls University of Tübingen, Tübingen, Germany; German Center for Diabetes Research, Neuherberg, Germany.

Insulin acts on the CNS to modulate behaviour and systemic metabolism. Disturbances in brain insulin action represent a possible link between metabolic and cognitive health. Current findings from human research suggest that boosting central insulin action in the brain modulates peripheral metabolism, enhancing whole-body insulin sensitivity and suppressing endogenous glucose production. Moreover, central insulin action curbs food intake by reducing the salience of highly palatable food cues and increasing cognitive control. Animal models show that the mesocorticolimbic circuitry is finely tuned in response to insulin, driven mainly by the dopamine system. These mechanisms are impaired in people with obesity, which might increase their risk of developing type 2 diabetes and associated diseases. Overall, current findings highlight the role of insulin action in the brain and its consequences on peripheral metabolism and cognition. Hence, improving central insulin action could represent a therapeutic option for people at an increased risk of developing metabolic and cognitive diseases.
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http://dx.doi.org/10.1016/S2213-8587(20)30113-3DOI Listing
June 2020

Brain insulin sensitivity is linked to adiposity and body fat distribution.

Nat Commun 2020 04 15;11(1):1841. Epub 2020 Apr 15.

Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Otfried-Müller-Str. 10, 72076, Tübingen, Germany.

Brain insulin action regulates eating behavior and energy fluxes throughout the body. However, numerous people are brain insulin resistant. How brain insulin responsiveness affects long-term weight and body fat composition in humans is still unknown. Here we show that high brain insulin sensitivity before lifestyle intervention associates with a more pronounced reduction in total and visceral fat during the program. High brain insulin sensitivity is also associated with less regain of fat mass during a nine year follow-up. Cross-sectionally, strong insulin responsiveness of the hypothalamus associates with less visceral fat, while subcutaneous fat is unrelated. Our results demonstrate that high brain insulin sensitivity is linked to weight loss during lifestyle intervention and associates with a favorable body fat distribution. Since visceral fat is strongly linked to diabetes, cardiovascular risk and cancer, these findings have implications beyond metabolic diseases and indicate the necessity of strategies to resolve brain insulin resistance.
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http://dx.doi.org/10.1038/s41467-020-15686-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7160151PMC
April 2020

Carotid Intima-Media Thickness is a Predictor of Subclinical Myocardial Damage in Men with Type 2 Diabetes Mellitus.

Exp Clin Endocrinol Diabetes 2020 Mar 4. Epub 2020 Mar 4.

Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Germany.

Background: Type 2 diabetes mellitus (T2DM) promotes the development of atherosclerosis and is a major risk factor for cardiovascular disease. High-sensitivity cardiac troponin I (hs-cTnI) assays fundamentally improved the diagnosis of myocardial injury and even enable the prediction of future cardiovascular events in the general population. However, data about the association of hs-cTnI with cardiovascular risk factors and carotid intima media thickness (cIMT) as a marker of atherosclerosis are limited, especially in patients with T2DM.

Methods: In this cross-sectional study we analyzed clinical and laboratory parameters of 234 patients (43% women) with T2DM and a median age of 65 years (interquartile range: 57-71). The median duration of diabetes mellitus was 10 years (6-17). Anthropometric data, blood pressure, glycemic parameters and lipid profiles were determined. Hs-cTnI plasma concentrations were measured on an ADVIA Centaur XPT immunoassay analyzer and cIMT was evaluated by high-resolution ultrasound.

Results: Hs-cTnI plasma concentrations were below the gender-specific 99  percentile in 93% of T2DM patients with a median concentration of 4.0 ng/l (interquartile range: 2.0-10.0). Hs-cTnI was significantly associated with gender, renal function and C-reactive protein in the entire study cohort. Gender-specific analyses revealed cIMT and renal function to be significantly associated with hs-cTnI in men. Contrary, only age was significantly associated with hs-cTnI in women.

Conclusion: In a real-world clinical setting in patients with T2DM, cIMT is a predictor of subclinical myocardial damage in men, but not in women.
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http://dx.doi.org/10.1055/a-1107-2657DOI Listing
March 2020

Dusp8 affects hippocampal size and behavior in mice and humans.

Sci Rep 2019 12 20;9(1):19483. Epub 2019 Dec 20.

Research Unit Neurobiology of Diabetes, Helmholtz Zentrum München, 85764, Neuherberg, Germany.

Dual-specificity phosphatase 8 (Dusp8) acts as physiological inhibitor for the MAPKs Jnk, Erk and p38 which are involved in regulating multiple CNS processes. While Dusp8 expression levels are high in limbic areas such as the hippocampus, the functional role of Dusp8 in hippocampus morphology, MAPK-signaling, neurogenesis and apoptosis as well as in behavior are still unclear. It is of particular interest whether human carriers of a DUSP8 allelic variant show similar hippocampal alterations to mice. Addressing these questions using Dusp8 WT and KO mouse littermates, we found that KOs suffered from mildly impaired spatial learning, increased locomotor activity and elevated anxiety. Cell proliferation, apoptosis and p38 and Jnk phosphorylation were unaffected, but phospho-Erk levels were higher in hippocampi of the KOs. Consistent with a decreased hippocampus size in Dusp8 KO mice, we found reduced volumes of the hippocampal subregions subiculum and CA4 in humans carrying the DUSP8 allelic variant SNP rs2334499:C > T. Overall, aberrations in morphology and behavior in Dusp8 KO mice and a decrease in hippocampal volume of SNP rs2334499:C > T carriers point to a novel, translationally relevant role of Dusp8 in hippocampus function that warrants further studies on the role of Dusp8 within the limbic network.
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http://dx.doi.org/10.1038/s41598-019-55527-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6925303PMC
December 2019